Abstract
Background
Guidelines recommend ≥2 weeks of antifungal therapy after candidemia clearance and for invasive candidiasis (IC). This post-hoc analysis evaluates Day 7 pooled data from the phase 2 STRIVE and phase 3 ReSTORE trials to explore early antifungal activity.
Methods
Adults with candidemia and/or IC received weekly rezafungin 400/200 mg or daily caspofungin 70/50 mg for ≤4 weeks. Efficacy was evaluated in the modified intent-to-treat population via all-cause mortality (ACM; primary endpoint; 20% noninferiority margin), mycological eradication, and time to negative blood culture (TTNBC) at days 7, 14, and 30 (TTNBC assessed only in patients with candidemia). Day 7 safety was evaluated in the safety population.
Results
Rezafungin was noninferior to caspofungin at each timepoint. Day 7 ACM rates were 7.9% (11/139) for rezafungin and 5.2% (8/155) for caspofungin (weighted difference [95% CI]: 3.0% [−3.7, 9.7]). Mycological eradication was similar between groups at all timepoints. Day 7 rates were 71.2% (99/139) and 65.2% (101/155), respectively (weighted difference [95% CI]: 6.6% [−4.0, 17.1]). Median (interquartile range) TTNBC was numerically shorter for rezafungin (22.3 [14.3–47.0] hours; caspofungin 26.3 [17.8–112.6] hours). Subgroup analyses suggested potential Day 7 benefits for rezafungin in patients with candidemia or C. albicans. Day 7 safety for rezafungin was consistent with previous reports.
Conclusions
Rezafungin was noninferior to caspofungin in candidemia and/or IC from Day 7, with shorter TTNBC in patients with candidemia. Subgroup analysis suggested a potential early benefit with rezafungin in some patients. Trials exploring shorter treatment durations for some patients are warranted.
Clinical trials registrations
NCT02734862 (STRIVE); NCT03667690 (ReSTORE).
Keywords: candidemia, early efficacy, invasive candidiasis, rezafungin, treatment duration
Post-hoc analysis of pooled STRIVE/ReSTORE data shows noninferiority of rezafungin to caspofungin for all-cause mortality from Day 7 and shorter TTNBC in patients with candidemia or candidemia with invasive candidiasis. Future trials should explore shorter treatment durations for some patients.
Due to high mortality rates, candidemia and invasive candidiasis (IC) pose a significant risk to affected patients [1–3] and can incur a considerable economic burden [4–6]. Guidelines recommend the timely administration of echinocandins as first-line treatment [7]. At least 2 weeks of echinocandin treatment is recommended after clearance of blood cultures in patients with candidemia and in patients with suspected IC who improve [7], although shorter courses may be considered in patients who demonstrate an early clinical response.
Rezafungin is a next-generation echinocandin approved for use in adults with candidemia and/or IC in several countries [8–11]. In the USA specifically, rezafungin is indicated in patients aged 18 years or older who have limited or no alternative options for the treatment of candidemia and IC [9]. The efficacy, safety, and tolerability of rezafungin in patients with candidemia and/or IC were demonstrated in the phase 2 STRIVE (NCT02734862) [12] and phase 3 ReSTORE (NCT03667690) [13] trials. STRIVE reported rezafungin to be well tolerated and efficacious [14], while ReSTORE demonstrated the noninferiority of rezafungin to caspofungin for global cure at Day 14 and all-cause mortality (ACM) at Day 30 [15].
Although structurally similar to other echinocandins, the distinct pharmacokinetic profile of rezafungin allows for once-weekly as opposed to once-daily dosing [16]. High, front-loaded dosing with rezafungin results in high concentrations of drug early in the course of treatment [14, 15, 17], which has the potential to drive early efficacy [18]. Data from the ReSTORE trial suggested a potential early treatment benefit with rezafungin [15]. Median time to negative blood culture (TTNBC) was approximately 3 hours shorter with rezafungin than with caspofungin (23.9 vs 27.0 hours, respectively) [15]. Prior literature on the use of micafungin and anidulafungin for candidemia and IC report a much longer time to clearance of cultures of 2–4 days [19–21].
Here, we present a post-hoc evaluation of the pooled STRIVE and ReSTORE data. We examine, for the first time, data from Day 7 in detail and compare Day 7 endpoints (ie, those after a single dose of rezafungin) with those at Days 14 and 30. We sought to identify any potential early, clinically meaningful differences in endpoints and assess patient subpopulations for whom a shorter duration of therapy may be appropriate.
METHODS
Patients and Study Design
Full methodology for the pooled analysis of data from STRIVE [14] and ReSTORE [15] has been reported [22].
Study Design
Both studies were multicenter, randomized, controlled, double-blind trials comparing the efficacy and safety of intravenous (IV) rezafungin and caspofungin [14, 15, 22]. Patients were adults aged ≥18 years who had systemic signs of candidemia and/or IC with mycological evidence of infection, in blood or a normally sterile site, within 96 hours before randomization. The trials were conducted in accordance with relevant country and local regulations, International Conference on Harmonization Good Clinical Practice Guidelines, and the Declaration of Helsinki. Study protocols and all amendments were approved by ethics committees or institutional review boards at participating sites. Written informed consent was provided by all patients or their legal representatives [22].
Dosing was largely comparable across both trials, facilitating data pooling. In the pooled groups, rezafungin was administered weekly at a dose of 400 mg on Day 1 and 200 mg on Day 8, with optional 200-mg doses given on Days 15 and 22 (in ReSTORE and patients with IC in STRIVE) [14, 15, 22]. Caspofungin was administered daily (70 mg on Day 1, then 50 mg/day thereafter for 3 to up to 21 days [patients with candidemia only in STRIVE] or 3 up to 28 days [in ReSTORE and patients with IC with or without candidemia in STRIVE]). After 3 days of treatment, oral stepdown therapy was permitted for eligible patients: to placebo in the case of rezafungin, or fluconazole in the case of caspofungin [22].
Endpoints
In the present post-hoc analysis of the pooled data, endpoints were assessed at Days 7, 14, and 30. The primary efficacy endpoint was the ACM rate, comprising the proportion of patients with candidemia and/or IC who died on or before the day of assessment, irrespective of cause, or who had unknown survival status. The secondary efficacy endpoint was the mycological eradication rate in patients with candidemia and/or IC. For patients with a positive baseline blood culture (ie, candidemia), the mycological eradication rate was defined as the proportion of patients with a negative blood culture on or before the day of assessment. For patients with a positive culture at baseline from a normally sterile site other than blood (ie, IC only), mycological eradication was either documented by negative culture (from the same site) or presumed (based on evaluation of clinical and radiological cure, if a specimen from the infected site was not available). Patients also had to be alive with no change in their antifungal therapy for candidemia and/or IC, and they had not to be lost to follow-up. Time to negative blood culture was an exploratory endpoint, defined as the time from the first dose of study drug to first negative blood culture, with no subsequent positive cultures, in patients with a positive blood culture (ie, candidemia) before randomization. Patients were censored from the TTNBC analysis if they had received an alternative antifungal drug for candidemia, died, or were lost to follow-up before having the negative blood culture. Subanalyses of endpoints were conducted by candidemia diagnosis, Candida species, and patients in the intensive care unit (ICU) at any point on or after randomization.
An additional exploratory analysis was also undertaken, pooling data from both treatment groups, to investigate the impact of baseline modified Acute Physiology and Chronic Health Evaluation II (APACHE II) score, an estimate of disease severity and mortality for patients in the ICU, on the efficacy endpoints.
Safety was evaluated at Day 7 via assessment of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 [22]. In STRIVE, adverse events were graded as mild, moderate, or severe, while in ReSTORE, events were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Adverse events in the pooled dataset were graded as mild (mild or grade 1), moderate (moderate or grade 2), or severe (severe or at or above grade 3).
Statistical Analysis
Efficacy endpoints are reported in the modified intent-to-treat (mITT) population (patients with confirmed Candida infection within 96 hours of randomization who received at least 1 dose of study drug, excluding patients from STRIVE who were not randomized to receive 400/200 mg rezafungin). Safety was assessed in the safety population, encompassing all patients who received at least 1 dose of study drug.
Efficacy endpoints were compared across groups using weighted treatment differences and corresponding 95% CIs, calculated using the Miettinen–Nurminen method, stratified by study and study part (in STRIVE). Noninferiority for ACM was assessed at a 20% noninferiority margin. Time to negative blood culture was analyzed using Kaplan–Meier methods and nominal P values determined using a log-rank test stratified by study and study part. The same methods were used for the subgroup analyses.
RESULTS
Patients
Across STRIVE and ReSTORE, the pooled mITT population consisted of 294 patients: 139 in the rezafungin group (46 from STRIVE and 93 from ReSTORE) and 155 (61 from STRIVE and 94 from ReSTORE) in the caspofungin group. Patient disposition has been reported previously [22].
The 2 treatment groups were generally well matched with respect to baseline characteristics (Table 1) [22]. Most patients in both groups had a modified APACHE II score of <20 (rezafungin: 84.7%; caspofungin: 82.9%) and a final diagnosis of candidemia only (rezafungin: 71.9%; caspofungin: 74.2%).
Table 1.
Pooled Baseline Characteristics (mITT Population)
| Characteristic | Rezafungin (n = 139) |
Caspofungin (n = 155) |
|---|---|---|
| Age, median (IQR) | 60 (49–71) | 62 (52–71) |
| Sex, n (%) | … | … |
| Male | 90 (64.7) | 90 (58.1) |
| Female | 49 (35.3) | 65 (41.9) |
| Race, n (%) | … | … |
| White | 95 (68.3) | 106 (68.4) |
| Asian | 24 (17.3) | 34 (21.9) |
| Black or African American | 11 (7.9) | 8 (5.2) |
| American Indian or Alaska Native | 1 (0.7) | 1 (0.6) |
| Native Hawaiian or other Pacific Islander | 0 | 0 |
| Other | 3 (2.2) | 2 (1.3) |
| Not reported | 5 (3.6) | 4 (2.6) |
| Ethnicity, n (%) | … | … |
| Not-Hispanic or not-Latino | 121 (87.1) | 141 (91.0) |
| Hispanic or Latino | 13 (9.4) | 10 (6.5) |
| Not reported | 5 (3.6) | 4 (2.6) |
| BMI, kg/m2, median (IQR) | (n = 133) 24.10 (20.76–28.69) |
(n = 144) 24.34 (21.12–27.65) |
| Final diagnosisa, n (%) | … | … |
| Candidemia only | 100 (71.9) | 115 (74.2) |
| Invasive candidiasisb | 39 (28.1) | 40 (25.8) |
| Positive Candida culture proximal to randomizationc | 53 (38.1) | 71 (45.8) |
| Catheter placementd, n/N (%) | … | … |
| Yes | 91/115 (79.1) | 107/130 (82.3) |
| Removed within 48 h of diagnosis | 24/115 (20.9) | 33/130 (25.4) |
| Modified APACHE II score, n/N (%) | … | … |
| ≥20 | 21/137 (15.3) | 26/152 (17.1) |
| <20 | 116/137 (84.7) | 126/152 (82.9) |
| Absolute neutrophil count at randomization, n (%) | … | … |
| <500 cells per µL | 7/135 (5.2) | 5/151 (3.3) |
| ≥500 cells per µL | 128/135 (94.8) | 146/151 (96.7) |
| Renal impairment category based on creatinine, n (%) | … | … |
| ≥60 mL/min (normal to mild) | 75 (54.0) | 83 (53.5) |
| <60 mL/min (moderate to severe) | 54 (38.8) | 59 (38.1) |
| Child–Pugh score category, n (%) | … | … |
| <7 | 0 | 1 (0.6) |
| ≥7 | 3 (2.2) | 9 (5.8) |
| No history of liver disease/not calculated | 136 (97.8) | 145 (93.5) |
Adapted from Thompson GR III, et al [22] under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/). Minor amendments have been made (terminology, to provide percentages correct to 1 decimal place, and addition of data for catheter placement) for the purposes of this publication.
Where the total number of evaluable patients in each group did not correspond to the total number of patients, numbers (N) are specified. Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; BMI, body mass index; IQR, interquartile range; mITT, modified intent-to-treat.
aFor ReSTORE, the final diagnosis was determined based on the radiological or tissue culture assessment, or both, through to Day 14; for STRIVE, the final diagnosis was the same as the baseline diagnosis.
bInvasive candidiasis with or without candidemia.
cDefined as a culture from blood drawn within 12 hours before randomization or within 72 hours after randomization, or a culture from another normally sterile site obtained within 48 hours prior to randomization or within 72 hours after randomization.
dFor ReSTORE, the population was the mITT population with a positive blood culture at baseline.
Efficacy
Rezafungin demonstrated noninferiority to caspofungin with respect to the primary pooled efficacy endpoint, ACM rate in patients with candidemia and/or IC, at all timepoints (ie, Days 7, 14, and 30; Table 2). At Day 7, ACM rates were 7.9% (11/139) in the rezafungin group and 5.2% (8/155) in the caspofungin group. Weighted treatment differences (95% CI) for rezafungin − caspofungin were 3.0% (−3.7, 9.7) at Day 7, 2.7% (−5.0, 10.5) at Day 14, and −1.5% (−10.7, 7.7) at Day 30. Subgroup analyses (Figure 1) showed that noninferiority for the ACM rate at Day 7 was maintained when data were evaluated in the subgroups of patients with candidemia (weighted treatment difference [95% CI]: 2.5% [−6.1, 11.1]) and patients with C. albicans (weighted treatment difference [95% CI]: 0.6% [−10.2, 11.3]).
Table 2.
Pooled Efficacy Endpoints at Days 7, 14, and 30 (mITT Population)
| Endpoint | Rezafungin (n = 139) |
Caspofungin (n = 155) |
Weighted Treatment Difference (95% CI) For Rezafungin − Caspofungin/P Value |
|---|---|---|---|
| Day 7 | |||
| ACM, n (%) | 11 (7.9) | 8 (5.2) | 3.0 (−3.7, 9.7) |
| Mycological eradication, n (%) | 99 (71.2) | 101 (65.2) | 6.6 (−4.0, 17.1) |
| TTNBCa,b, n | 109 | 122 | … |
| Patients with negative blood culture, n (%) | 94 (86.2) | 90 (73.8) | … |
| Patients censoredc, n (%) | 15 (13.8) | 32 (26.2) | … |
| TTNBC, median (IQR), hours | 22.3 (14.3–47.0) | 26.3 (17.8–112.6) | P = .0049 |
| Day 14 | |||
| ACM, n (%) | 16 (11.5) | 14 (9.0) | 2.7 (−5.0, 10.5) |
| Mycological eradication, n (%) | 100 (71.9) | 106 (68.4) | 4.3 (−6.2, 14.7) |
| TTNBCa,b, n | 109 | 122 | … |
| Patients with negative blood culture, n (%) | 99 (90.8) | 99 (81.1) | … |
| Patients censoredc, n (%) | 10 (9.2) | 23 (18.9) | … |
| TTNBC, median (IQR), hours | 22.3 (14.3–47.0) | 26.3 (17.8–112.6) | P = .0051 |
| Day 30 | |||
| ACM, n (%) | 26 (18.7) | 30 (19.4) | −1.5 (−10.7, 7.7) |
| Mycological eradication, n (%) | 92 (66.2) | 92 (59.4) | 7.8 (−3.1, 18.6) |
| TTNBCa,b, n | 109 | 122 | … |
| Patients with negative blood culture, n (%) | 99 (90.8) | 99 (81.1) | … |
| Patients censoredc, n (%) | 10 (9.2) | 23 (18.9) | … |
| TTNBC, median (IQR), hours | 22.3 (14.3–47.0) | 26.3 (17.8–112.6) | P = .0051 |
For ACM and mycological eradication, 2-sided 95% CIs for the weighted treatment difference in estimated rates (rezafungin − caspofungin) were calculated using the Miettinen–Nurminen method, stratified by study and study part. For TTNBC, median values and IQR were estimated based on Kaplan–Meier methods; P values are from a log-rank test, stratified by study and study part.
Abbreviations: ACM, all-cause mortality; IQR, interquartile range; mITT, modified intent-to-treat; TTNBC, time to negative blood culture.
aBlood culture sampling was repeated daily (preferred) or every 2 days until the first negative culture result.
bOnly includes patients with a positive Candida blood culture before randomization.
cPatients were censored if they had received an alternative antifungal drug for candidemia, died, or were lost to follow-up prior to having the negative blood culture.
Figure 1.
Difference in all-cause mortality rate at Day 7 between rezafungin and caspofungin by patient subgroup (mITT population). Units are % (95% CI). Percentages were calculated using the total number of patients in each treatment group (n) as the denominator. All-cause mortality was defined as patients who died on or before Day 7 irrespective of cause, or had unknown survival status. Two-sided 95% CIs for the weighted treatment difference in estimated all-cause mortality rate (rezafungin − caspofungin) were calculated using the Miettinen–Nurminen method, stratified by study and study part. Abbreviations: ICU, intensive care unit; mITT, modified intent-to-treat.
For mycological eradication rates in patients with candidemia and/or IC, no meaningful difference was observed between treatment groups at Day 7 (Table 2). Eradication rates at Day 7 were 71.2% (99/139) and 65.2% (101/155) in the rezafungin and caspofungin groups, respectively, for a weighted treatment difference (95% CI) of 6.6% (−4.0, 17.1). Rates at Days 14 and 30 were also similar between groups. The similarity of mycological eradication rates at Day 7 was maintained in the candidemia subgroup (weighted treatment difference [95% CI]: 6.5% [−5.3, 18.4]) and the C. albicans subgroup (weighted treatment difference [95% CI]: 0.7% [−15.0, 16.4]) (Figure 2).
Figure 2.
Difference in mycological eradication rate at Day 7 between rezafungin and caspofungin by patient subgroup (mITT population). Units are % (95% CI). Percentages were calculated using the total number of patients in each treatment group (n) as the denominator. Mycological eradication was defined, in patients with a positive baseline culture, as a negative blood culture on or before the day of assessment. For patients with a positive culture at baseline from a normally sterile site other than blood, mycological eradication was either documented by negative culture (from the same site) or presumed (based on evaluation of clinical and radiological cure, if a specimen from the infected site was not available). Patients also had to be alive with no change in their antifungal therapy for candidemia and/or invasive candidiasis and not be lost to follow-up. Two-sided 95% CIs for the weighted treatment difference in estimated mycological eradication rate (rezafungin – caspofungin) were calculated using the Miettinen–Nurminen method, stratified by study and study part. Abbreviations: ICU, intensive care unit; mITT, modified intent-to-treat.
For TTNBC, rezafungin resulted in a numerically shorter median (interquartile range; IQR) TTNBC compared with caspofungin (22.3 [14.3–47.0] vs 26.3 [17.8–112.6] hours, respectively; nominal P = .0049 at Day 7; Table 2, Figure 3). At Day 7, 86.2% (94/109) of patients in the rezafungin group and 73.8% (90/122) of those in the caspofungin group had negative blood cultures. At Day 14, these values were 90.8% (99/109) and 81.1% (99/122), respectively, with no further change at Day 30.
Figure 3.
Time to negative blood culture for rezafungin versus caspofungin by patient subgroup (mITT population).a TTNBC was defined as the time from the first dose of study drug to first negative blood culture, with no subsequent positive cultures, in patients with a positive blood culture before randomization. Blood culture sampling was repeated daily (preferred) or every 2 days until the first negative culture result. Patients were censored if they had received an alternative antifungal drug for candidemia, died, or were lost to follow-up prior to having the negative blood culture. Median values and IQR are presented, estimated based on Kaplan–Meier methods. Presented P values (calculated at Day 7) are from a log-rank test, stratified by study and study part. Abbreviations: IQR, interquartile range; mITT, modified intent-to-treat; TTNBC, time to negative blood culture. aSubanalyses at Day 7 were limited by small numbers.
In subgroup analyses, rezafungin resulted in a numerically shorter median (IQR) TTNBC in patients with candidemia, compared with caspofungin (22.3 [13.5–43.5] vs 26.3 [17.8–112.6] hours, respectively; nominal P = .0075 at Day 7) (Figure 3). Median (IQR) TTNBC was similar between treatment groups in patients with C. albicans (rezafungin: 21.7 [14.3–43.0] hours; caspofungin: 22.2 [17.8–68.6] hours; nominal P = .4934 at Day 7). For patients with C. glabrata, median (IQR) TTNBC was 19.9 (13.5–48.3) hours in the rezafungin group and 30.3 (19.6–not estimable) hours in the caspofungin group (nominal P = .0542 at Day 7). Median TTNBC was not estimable for the caspofungin group in the ICU subgroup, meaning treatment group comparisons could not be drawn. In all subgroups, higher proportions of negative blood cultures were achieved in the rezafungin group than in the caspofungin group at Day 7. In patients with candidemia, the proportion was 86.0% (86/100) for rezafungin compared with 73.9% (85/115) for caspofungin. For those with C. albicans, rates were 94.6% (35/37) and 83.7% (41/49) in the rezafungin and caspofungin groups, respectively. In the case of C. glabrata, rates were 87.1% (27/31) with rezafungin and 67.9% (19/28) with caspofungin. For patients in the ICU, rates were 76.9% (10/13) and 28.6% (2/7), respectively.
Efficacy data at Day 14 and Day 30 for the subgroup analyses are presented for comparison in Supplementary Tables 1–4.
The exploratory analysis of pooled data from both treatment groups by modified APACHE II score revealed numerically lower ACM rates at Day 7 in patients with a baseline score of <20 versus ≥20 (Table 3). While ACM rates at Days 14 and 30 were numerically lower and mycological eradication rates at all 3 timepoints were numerically higher in patients with a baseline score of <20 versus ≥20, differences were not significant based on the 95% CIs for the weighted differences. Median (IQR) time to negative blood culture was 23.1 (15.9–58.8) hours in patients with a baseline modified APACHE II score of <20 and 20.1 (15.0–62.0) hours in those with a baseline score of ≥20.
Table 3.
Pooled Rezafungin and Caspofungin Efficacy Endpoints by Modified APACHE II Score (mITT Population)
| Endpoint | Modified APACHE II Score | Weighted Difference (95% CI)/P Value | |
|---|---|---|---|
| <20 (n = 224) |
≥20 (n = 45) |
||
| Day 7 | |||
| ACM, n (%) | 10 (4.5) | 8 (17.8) | −19.2 (−30.7, −7.8) |
| Mycological eradication, n (%) | 153 (68.3) | 29 (64.4) | 6.4 (−8.0, 20.8) |
| TTNBCa,b, n | 169 | 41 | … |
| Patients with negative blood culture, n (%) | 139 (82.2) | 31 (75.6) | … |
| Patients censoredc, n (%) | 30 (17.8) | 10 (24.4) | … |
| TTNBC, median (IQR), hours | 23.1 (15.9–58.8) | 20.1 (15.0–62.0) | P = .8005 |
| Day 14 | |||
| ACM, n (%) | 17 (7.6) | 11 (24.4) | −20.5 (−33.0, −7.9) |
| Mycological eradication, n (%) | 159 (71.0) | 28 (62.2) | 10.9 (−3.5, 25.3) |
| TTNBCa,b, n | 169 | 41 | … |
| Patients with negative blood culture, n (%) | 150 (88.8) | 33 (80.5) | … |
| Patients censoredc, n (%) | 19 (11.2) | 8 (19.5) | … |
| TTNBC, median (IQR), hours | 23.1 (15.9–58.8) | 20.1 (15.0–62.0) | P = .9043 |
| Day 30 | |||
| ACM, n (%) | 37 (16.5) | 14 (31.1) | −16.8 (−30.2, −3.4) |
| Mycological eradication, n (%) | 145 (64.7) | 24 (53.3) | 13.0 (−1.7, 27.7) |
| TTNBCa,b, n | 169 | 41 | … |
| Patients with negative blood culture, n (%) | 150 (88.8) | 33 (80.5) | … |
| Patients censoredc, n (%) | 19 (11.2) | 8 (19.5) | … |
| TTNBC, median (IQR), hours | 23.1 (15.9–58.8) | 20.1 (15.0–62.0) | P = .9043 |
For ACM and mycological eradication, 2-sided 95% CIs for the weighted treatment difference in estimated rates (modified APACHE II score <20 − modified APACHE II score ≥20) were calculated using the Miettinen–Nurminen method, stratified by study and study part. For TTNBC, median values and IQR were estimated based on Kaplan–Meier methods; P values are from a log-rank test, stratified by study and study part.
Abbreviations: ACM, all-cause mortality; APACHE, Acute Physiology and Chronic Health Evaluation; IQR, interquartile range; mITT, modified intent-to-treat; TTNBC, time to negative blood culture.
aBlood culture sampling was repeated daily (preferred) or every 2 days until the first negative culture result.
bOnly includes patients with a positive Candida blood culture before randomization.
cPatients were censored if they had received an alternative antifungal drug for candidemia, died, or were lost to follow-up prior to having the negative blood culture.
Safety
The safety profiles of rezafungin and caspofungin at Day 7 were similar and are summarized in Supplementary Table 5. Overall, 70.9% (107/151) of patients receiving rezafungin and 60.8% (101/166) of those receiving caspofungin experienced TEAEs, with 9.9% (15/151) and 6.6% (11/166) experiencing study drug-related TEAEs, respectively. The most common TEAEs (reported in at least 5% of patients in either group) were hypokalemia, diarrhea, and anemia. Severe TEAEs occurred at similar rates between groups (rezafungin: 20.5% [31/151]; caspofungin: 19.9% [33/166]). Study drug-related SAEs occurred in one patient receiving rezafungin and 2 patients receiving caspofungin. Serious adverse events led to death in 7.9% (12/151) of patients in the rezafungin group and 7.2% (12/166) of those in the caspofungin group; none of these deaths was study drug related.
DISCUSSION
This post-hoc analysis of pooled data from the STRIVE and ReSTORE trials assessed the efficacy and safety of rezafungin and caspofungin in patients with candidemia and/or IC at Days 7, 14, and 30. Rezafungin was noninferior to caspofungin for the primary efficacy endpoint of ACM rate at all timepoints. Subgroup analyses also demonstrated noninferiority for the ACM rate at Day 7 in patients with candidemia and in those with C. albicans. Mycological eradication rates were broadly similar between treatment groups across timepoints, although rates at Day 7 for patients in the ICU and patients with C. glabrata were numerically higher with rezafungin than with caspofungin. In exploratory analyses, rezafungin had a shorter TTNBC than caspofungin, indicating early and sustained antifungal activity. As expected, ACM rates at Day 7 were higher in patients with more severe illness, as indicated by a modified APACHE II score ≥20. The safety profile of rezafungin at Day 7 was similar to that of caspofungin. These findings largely support those of earlier analyses [14, 15, 22].
Previous analyses suggest a potential early treatment benefit of rezafungin [15, 22]. The present analysis supports this observation, with rezafungin exhibiting efficacy and noninferiority to caspofungin for the ACM rate as early as Day 7. Rezafungin also had a numerically shorter TTNBC compared with caspofungin. In an earlier report of the pooled analysis of the STRIVE and ReSTORE data, rezafungin was associated with numerically higher rates of mycological eradication versus caspofungin by Day 5 [22]. In the present analysis, eradication rates between the 2 groups were similar at Day 7 and at later timepoints, adding further support to earlier data and suggesting that rezafungin may be efficacious within the first week.
Exploratory subgroup analyses also suggested potential early treatment benefits in specific subpopulations. In patients with C. glabrata at baseline, numerically higher ACM and mycological eradication rates were seen with rezafungin versus caspofungin at Day 7, although interpretation of these data is limited by the small sample size. A shorter TTNBC was also observed, although this was not statistically significant on the exploratory log-rank test. For patients with candidemia, rezafungin was noninferior to caspofungin for the ACM rate at Day 7, with a shorter TTNBC (nominal P = .0075 at Day 7). Analysis of patients in the ICU was also limited by the small sample size but was suggestive of increased mycological eradication rates and higher rates of negative blood cultures with rezafungin compared with caspofungin at Day 7. These findings support data from a previous post-hoc pooled analysis of the STRIVE/ReSTORE data from patients in the ICU, which showed a higher mycological eradication rate at Day 5 for rezafungin (78.3% for rezafungin vs 59.7% for caspofungin) and that rezafungin had a shorter median (IQR) TTNBC than caspofungin in these patients (18 [12.6–43.0] hours for rezafungin vs 38 [15.9–211.3] hours for caspofungin) [23]. Taken together, the data suggest potential early treatment benefits with rezafungin in this patient group.
The potential early treatment benefit of rezafungin may be due to its distinct pharmacokinetic profile and high front-loaded dose [16, 24]. Such characteristics, which allow high initial plasma concentrations, are generally favored and may help prevent the development of drug-resistant Candida species [16, 22, 25]. C. glabrata, in particular, has a propensity for drug-resistant mutations [26, 27]. Rezafungin has shown a high probability of target attainment against C. glabrata following a single 400-mg dose [25, 28], and in vitro characterization has demonstrated a low rate of resistance to rezafungin in Candida species including C. glabrata [29]. Here, we show efficacy of rezafungin in patients with C. glabrata infections as early as Day 7, following a single 400-mg dose, with improved rates of mycological eradication and a favorable decrease in TTNBC.
In the first 7 days of treatment, the safety profile of rezafungin was comparable to that of caspofungin and to the overall safety profile of rezafungin reported previously [14, 15, 22]. The most frequent TEAEs reported in this analysis were hypokalemia, diarrhea, and anemia. A good safety profile for rezafungin is paramount, especially in the context of its weekly dosing regimen, as treatment cannot be aborted with ease in the event of adverse events.
This pooled analysis is subject to limitations. Firstly, the analysis is post hoc, and the STRIVE and ReSTORE trials were not specifically designed to compare endpoints at Day 7 with other timepoints; therefore, the data discussed are exploratory only. Additionally, patient populations in practice may differ from those in the STRIVE and ReSTORE trials. The ICU subpopulation in this analysis is small, which may limit the usefulness of the data. However, tentative conclusions can be made in conjunction with the previous pooled analysis of patients in the ICU [23]. Additionally, some definitions differed between the STRIVE and ReSTORE trials and adverse events were graded differently [22]. However, these differences were addressed and controlled for in the design of the pooled analysis. The main strength of this analysis lies in the pooling of datasets, providing larger, more robust populations for the subgroup analyses. Thus, the pooled data provide an important opportunity for exploratory analyses of optimal rezafungin treatment duration, and the findings could inform future study design. If this early treatment benefit of rezafungin is borne out, it could mean that clinical efficacy may be obtained following a single 400-mg dose. An early treatment benefit has the potential for fewer patient catheterizations and infusions, improved compliance, and a reduced resource burden [28]. Further targeted assessments are needed to evaluate the feasibility of short-course therapy, such as the planned study of 7- versus 14-day antifungal therapy for uncomplicated candidemia (NCT06907992) [30].
CONCLUSIONS
This post-hoc, signal-finding analysis of pooled data from the STRIVE and ReSTORE trials further supports the efficacy and safety of rezafungin in the treatment of candidemia and IC. Rezafungin was noninferior to caspofungin for the ACM rate from as early as Day 7 and had a shorter TTNBC, potentially suggesting an early treatment benefit reflective of rezafungin's pharmacokinetic profile that facilitates front-loaded doses. Exploratory subgroup analyses showed rezafungin to have a shorter TTNBC in patients with candidemia and in those with C. glabrata. Overall, these data provide evidence of early antifungal activity and offer a promising foundation for future investigation of shorter treatment durations in specific patient populations.
Supplementary Material
Notes
Author Contributions . L. O. -Z., O. A. C., and P. G. P. contributed to the design of the study and analyzed the data. L. O. Z. and G. R. T. contributed to the collection of data. L. O. -Z., G. R. T., J. A. A., J. A. M., M. R., A. S., and O. A. C. contributed to data analysis or interpretation. All authors reviewed and critically revised the manuscript, approved the final draft, and are accountable for the accuracy and integrity of the report.
Acknowledgments . We thank all patients and investigators involved in the study. Medical writing support, including development of drafts in consultation with the authors, collating author comments, copyediting, fact checking, and referencing, was provided by Anna Munro, PhD, and Caroline Greenwood, BSc (Hons), ISMPP, CMPP, at Aspire Scientific Limited (Manchester, UK). Funding for medical writing support for this article was provided by CorMedix Therapeutics (Parsippany, NJ, USA).
Data availability . Study protocols are provided at ClinicalTrials.gov (STRIVE: https://clinicaltrials.gov/study/NCT02734862; ReSTORE: https://clinicaltrials.gov/study/NCT03667690). Access to anonymized data can be requested by contacting medical-operations@mundipharma.com. Requests for data can be made beginning 9 months and ending 36 months following article publication. Each request will be reviewed by the sponsor for scientific merit.
Financial support. This work was supported by CorMedix Therapeutics (Parsippany, NJ, USA).
Contributor Information
Luis Ostrosky-Zeichner, Division of Infectious Diseases, McGovern Medical School, Houston, Texas, USA.
Jalal A Aram, CorMedix Therapeutics, Parsippany, New Jersey, USA.
Mark Redell, CorMedix Therapeutics, Parsippany, New Jersey, USA.
George R Thompson, III, University of California Davis Medical Center, Sacramento, California, USA.
Oliver A Cornely, University of Cologne, Faculty of Medicine and University Hospital Cologne (Institute of Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases [CECAD]; Department I of Internal Medicine, Division of Infectious Diseases, Excellence Center for Medical Mycology [ECMM] and Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf [CIO ABCD]; and Clinical Trials Center Cologne [ZKS Köln]), Cologne, Germany; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany.
James A McKinnell, Torrance Memorial Medical Center, Los Angeles, California, USA.
Andrej Spec, Washington University School of Medicine in St.Louis, St. Louis, Missouri, USA.
Peter G Pappas, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
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